Understanding, managing and treating infectious disease in the long-term requires not just an understanding of the infectious agent, but also of the underlying genetics governing susceptibility of the host. This includes genes of the adaptive immune system, but equally important are those factors that interact directly with viral macromolecules either as positive cofactors for replication or as intrinsic host mechanisms for evading or attenuating infection. Variability in susceptibility to infection, disease course and pathogenesis is due in large part to the combined effects of genetic variation at multiple loci. The TRIM5alpha protein functions as an intrinsic inhibitor of retroviral replication, and the primate TRIM5 locus displays an unusually high degree of interspecies divergence, consistent with an evolutionary history of strong positive selection. We have discovered that extensive within-species variation, or polymorphism, exists in the TRIM5alpha coding sequences of two geographically distinct species of old world monkeys of particular relevance to HIV/AIDS research, rhesus macaques and sooty mangabeys. The specific aims of this proposal are unified by the goal of exploiting the extensive, naturally occurring adaptive variations in nonhuman primates to gain insight into the structure and function of TRIM5alpha, and to determine the extent of TRIM5alpha's influence on viral replication and disease progression in vivo.